NMDARs typically contain a GluN1 subunit in addition to GluN2A-GluN2D subunits. Stimulation of one or more of the subunits are thought to be beneficial for the treatment of cognitive dysfunctions as well as other conditions dependent on synaptic plasticity such as motor retraining and rehabilitation after ischemic insult, traumatic brain injury, and conditions that involve impairment of movement, speech, vision, or other functions controlled by the brain. See Traynelis et al., Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev, 2010, 62:405-496. See also Hardingham & Bading, Synaptic versus extra-synaptic NMDA receptor signaling: implications for neurodegenerative disorders, Nat Rev, Neurosci, 2010; 11:682-696; Tang et al., Genetic enhancement of learning and memory in mice, Nature, 401, 63-69 (1999); and Brigman et al., Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci, 2010, 30, 4590-4600.
Tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors are reported in Santangelo et al., J Med Chem, 2013, 56(13):5351-81. See also US Published Application 2014/0275529; US 2012/0028977; Acker et al., Mol Pharmacol, 2011, 80(5):782-95; and Zimmerman et al., J Med Chem, 2014, 57(6):2334-56.
References cited herein are not an admission of prior art.